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Safety of liposomal cytarabine CNS prophylaxis in children, adolescent and young adult hematopoietic stem cell transplant recipients with acute leukemia and non-Hodgkin lymphoma

Bone Marrow Transplantation volume 51, pages 1249–1252 (2016)Cite this article

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Leukemia and lymphomatous meningitis remains a unique concern in recurrent hematological malignancies associated with a high risk of central nervous system (CNS) involvement. The incidence of CNS relapses of leukemia after hematopoietic stem cell transplantation (HSCT) ranges from <5% among patients without a history of CNS disease and up to 27% among patients with prior CNS involvement pre-HSCT. There are conflicting studies as to the effectiveness of post-HSCT intrathecal (IT) chemotherapy prophylaxis in preventing CNS recurrence. Some studies have shown significantly higher recurrence rates in patients at risk of CNS relapse, whereas others have been unable to show much of a difference.1 These results likely reflect differences in patient populations as well as prophylactic strategies. However, there is a paucity of prospective data to truly compare the results of different prophylactic strategies. In addition, agents that have been shown to be effective in the treatment and prevention of leukemia or lymphoma meningeal disease require frequent administration in order to maintain appropriate cytotoxic concentrations. Liposomal cytarabine is a sustained release liposomal formulation of cytarabine approved for IT or intraommaya treatment of recurrent lymphomatous meningitis that allows for sustained release of cytarabine with prolonged therapeutic concentration and thus prolonged drug exposure of up to 8 days in children and 14 days in adults.2, 3, 4 The use of liposomal cytarabine could potentially overcome some of the barriers to post-HSCT administration of CNS prophylaxis and may provide for improved outcome results. The primary objectives of this single-institution study were to determine the safety and tolerability of liposomal cytarabine as prophylaxis prior to and following HSCT in pediatric recipients with acute leukemia and non-Hodgkin lymphoma at risk of CNS recurrence post HSCT.

All patients aged 2–25 years with a histologically proven diagnosis of acute leukemia (ALL or AML) or non-Hodgkin lymphoma (lymphoblastic lymphoma, Burkitt lymphoma and diffuse large B-cell lymphoma) who underwent either autologous or allogeneic HSCT and considered to be at risk of a CNS relapse either due to known prior history of leptomeningeal disease or risk for future recurrence were eligible to receive liposomal cytarabine prophylaxis prospectively. Risk of CNS recurrence was determined based on the number of relapse and underlying biological risk factors of primary disease. HSCT protocols were approved by the local institutional review board, and all patients signed informed consent. Conditioning regimens were largely protocol driven and disease specific and consisted of both myeloablative conditioning (n=19, 76%) and reduced toxicity conditioning (n=5, 24%) selected according to the patient’s disease status, organ function and performance status as we have previously described.5, 6, 7 Fifteen patients received a TBI (1200 cGy)-containing conditioning regimen. Six patients received an additional CNS boost of up to 1200 cGy. Acute GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil with dosage adjustment to maintain safe and therapeutic blood levels and utilized standard supportive care measures as we have previously described.8, 9, 10 All patients developing ⩾Grade II acute GVHD received systemic corticosteroid therapy (minimum equivalent 2 mg/kg of prednisone per day). Commercial supply of liposomal cytarabine (DepoCyt, Sigma-Tau Pharmaceuticals, Inc, Gaithersburg, MD, USA) was utilized from single-use 5-mL vials containing 50 mg (10 mg/mL) each. The appropriate dose (35 mg for children <21 years or 50 mg⩾21 years) was administered IT either via lumbar puncture or through an intraventricular ommaya reservoir. All patients received concurrent dexamethasone (0.15 mg/kg/dose (maximum 4 mg/dose) PO BID) treatment starting the day of and for 5 days after IT administration of the drug to prevent arachnoiditis as previously described.2 All patients received at least one dose of liposomal cytarabine either prior to or during HSCT conditioning. Some patients received maintenance therapy, which was then administered a minimum of once post HSCT with subsequent dosing allowed every 3 months post HSCT for up to 1 year. CSF studies, including cell counts, protein, glucose and cytology, were obtained prior to each dose of liposomal cytarabine. Brain magnetic resonance imaging and/or computed tomographic scan for evaluation of CNS disease status were obtained for patients with positive CNS findings or as clinically indicated. Toxicities are reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE 4.0). All patients were assessed for toxicity if they received at least one dose of liposomal cytarabine.

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Authors and Affiliations

  1. Department of Pediatrics, New York Medical College at Westchester Medical Center, Valhalla, NY, USA

    J Hochberg, L Harrison, E Morris, O Militano, P Brand, S Fabricatore, K Wolownik & M S Cairo

  2. Department of Medicine, New York Medical College at Westchester Medical Center, Valhalla, NY, USA

    M S Cairo

  3. Department of Pathology, New York Medical College at Westchester Medical Center, Valhalla, NY, USA

    M S Cairo

  4. Department of Microbiology and Immunology, New York Medical College at Westchester Medical Center, Valhalla, NY, USA

    M S Cairo

  5. Department of Cell Biology and Anatomy, New York Medical College at Westchester Medical Center, Valhalla, NY, USA

    M S Cairo

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Correspondence to M S Cairo.

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MS Cairo, MD receives research funding and has served on the Advisory Board of Sigma Tau Pharmaceuticals Inc. The other authors declare no conflict of interest.

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Hochberg, J., Harrison, L., Morris, E. et al. Safety of liposomal cytarabine CNS prophylaxis in children, adolescent and young adult hematopoietic stem cell transplant recipients with acute leukemia and non-Hodgkin lymphoma. Bone Marrow Transplant 51, 1249–1252 (2016). https://doi.org/10.1038/bmt.2016.100

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